Although cure rates for childhood cancers have steadily improved, survival rates for sarcoma cancers over the last decade have reached a plateau. For these children with advanced disease, prognosis for a 5- year survival remains dismally low. Eradicating the remaining cases of childhood sarcomas will require additional knowledge of the underlying mechanisms driving advanced disease so as to potentially develop novel therapeutic strategies. The NF-?B signaling pathway is commonly altered in human cancers and shown to contribute to the initiation and progression of tumorigenesis. NF-?B is therefore considered as an attractive therapeutic target in the treatment of solid and hematopoietic cancers and several classes of inhibitor compounds are currently being developed. Our laboratory recently established a link between NF-?B signaling and rhabdomyosarcoma and similar findings were reported in osteosarcoma, suggesting that NF-?B signaling may contribute to the development of childhood sarcomas. How this occurs and whether NF-?B inhibition is efficacious in these tumors is the basis of this proposal. Our published and preliminary data suggest that activation of NF-?B in sarcomas is mediated by the canonical (classical) NF-?B pathway, and that non-canonical (alternative) signaling, which is usually active in normal differentiated tissue, is downregulated in transformed cells. We also show that sarcomas associate with mitochondrial dysfunction. These data are suggestive that sarcomas exhibit a metabolic shift, reminiscent of the Warburg effect. Since we show that alternative NF-?B signaling regulates mitochondria and oxidative phosphorylation through PGC-1, while classical NF-?B signaling along with mTOR and STATS coordinate the induction of glycolytic genes, indicate that NF-KB contributes to sarcomagenesis by altering cellular metabolism through promotion of the Warburg effect. To test this hypothesis, the following three specific aims will be performed: 1) Determine the disease relevance of PGC-1 regulation by NF-?B in the Warburg effect; 2) Elucidate the significance of NF-?B crosstalk with mTOR, STATS in altering metabolism of sarcomas, and 3) Test the therapeutic benefit of inhibiting classical NF-?B in mouse models of sarcomas. Results from these studies, and those described in separate projects of this P01 application, are likely to yield significant mechanistic insight into the therapeutic benefit of targeting NF-?B for the treatment of childhood sarcomas.